About 11,000 new cases of traumatic spinal cord injury (SCI) are reported in the United States annually, primarily affecting young adults [Wosnick, J., Baumann, M. D., Shoichet, M. S., Tissue Therapy in the Central Nervous System, in Principles of Regenerative Medicine, A. Atala, Lanza, R., Thomson, J. A., Nerem, R. M., eds., Editor. 2007, Elsevier: New York]. A majority of these cases are compression injuries wherein the cord is bruised under displacement of the spinal column, resulting in formation of a cystic cavity in the days after injury. As tissue degenerates, the degree of paralysis increases, causing further permanent loss of motor control and sensory perception. For this reason compression injuries are normally described as occurring in two stages, the immediate primary injury and subsequent secondary injury. Various treatment strategies are being developed with a view of limiting degeneration after the primary injury and/or promoting regeneration after secondary injury. Currently, however, there is no standard clinical treatment, other than application of methylprednisolone, the efficacy of which is still debated [Miller, S. M., Methylprednisolone in acute spinal cord injury: a tarnished standard. J Neurosurg Anesthesiol, 2008. 20(2): p. 140-2; Rozet, I., Methylprednisolone in acute spinal cord injury: is there any other ethical choice? J Neurosurg Anesthesiol, 2008. 20(2): p. 137-9]. Similarly, there is no standard of care for traumatic brain injury or stroke. For example, there is no cure for stroke, and the only FDA approved treatment is tissue plasminogen activator (tPA), a thrombolytic agent with limited therapeutic benefit [Stroke and cerebrovascular accidents. World Health Organization, Circulation, 2009].
Therapies designed to enhance cell survival during the trauma of secondary injury are focused on the hours to days following the primary injury and seek to limit vascular damage, excitotoxicity, and the inflammatory response around the injury site [Ramer, L. M., M. S. Ramer, and J. D. Steeves, Setting the stage for functional repair of spinal cord injuries: a cast of thousands. Spinal Cord, 2005. 43(3): p. 134-61.]. Neuroprotective strategies target one or more of these mechanisms with the goal of minimizing the death of motor and sensory neurons. For example, methylprednisolone targets acute inflammation and inhibits lipid peroxidation [Bracken, M. B., et al., Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study. J Neurosurg, 1992. 76(1): p. 23-31], while the sodium channel antagonist NBQX minimizes excitotoxicity [Li, Y., et al., Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine. Psychopharmacology (Berl), 1997. 134(3): p. 266-76] and nimodipine limits vasospasm [Scriabine, A., T. Schuurman, and J. Traber, Pharmacological basis for the use of nimodipine in central nervous system disorders. Faseb J, 1989. 3(7): p. 1799-806].
Neuroregenerative therapies enhance axonal outgrowth by either direct action or suppression of the inhibitory environment after injury. For example, numerous neurotrophins stimulate proliferation and regeneration, including: nerve growth factor [Romero, M. I., et al., Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J Neurosci, 2001. 21(21): p. 8408-16], brain derived neurotrophic factor [Tobias, C. A., et al., Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration. Exp Neurol, 2003. 184(1): p. 97-113], epidermal growth factor (EGF) [Kitchens, D. L., E. Y. Snyder, and D. I. Gottlieb, FGF and EGF are mitogens for immortalized neural progenitors. J Neurobiol, 1994. 25(7): p. 797-807] and basic fibroblast growth factor (FGF-2) [Bikfalvi, A., et al., Biological roles of fibroblast growth factor-2. Endocr Rev, 1997. 18(1): p. 26-45]. FGF-2 has also been reported to prevent neuronal cell death [Lee, T. T., et al., Neuroprotective effects of basic fibroblast growth factor following spinal cord contusion injury in the rat. J Neurotrauma, 1999. 16(5): p. 347-56; 13; Teng, Y. D., et al., Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. J Neurosci, 1999. 19(16): p. 7037-47] and promote angiogenesis [Loy, D. N., et al., Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat. J Comp Neurol, 2002. 445(4): p. 308-24]. The family of antibodies targeting NogoA [Schwab, M. E., Nogo and axon regeneration. Curr Opin Neurobiol, 2004. 14(1): p. 118-24], rho kinase inhibitors [McKerracher, L. and H. Higuchi, Targeting Rho to stimulate repair after spinal cord injury. J Neurotrauma, 2006. 23(3-4): p. 309-17] and cyclic AMP [Hannila, S. S. and M. T. Filbin, The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp Neurol, 2008. 209(2): p. 321-32] are well known anti-inhibitory molecules that act by blocking or overriding the inhibitory environment present post-injury. Similarly, chondroitinase abc requires local delivery as it cannot cross the blood-spinal cord barrier (or the blood-brain barrier) and requires sustained delivery, which is not easily obtained by other delivery methods. Chondroitinase abc acts to degrade the chondroitin sulfate proteoglycan present in the injured central nervous system and thereby facilitates axonal regeneration. These molecules are often delivered for extended periods, ranging from 7-28 days.
Whether neuroprotective or neuroregenerative, delivery is limited to local strategies as most molecules are unable to cross the blood-spinal cord barrier and blood-brain barrier, confounding systemic delivery. Current local delivery strategies are inadequate: bolus delivery often results in rapid clearance due to cerebrospinal fluid flow in the intrathecal space [Terada, H., et al., Reduction of ischemic spinal cord injury by dextrorphan: comparison of several methods of administration. J Thorac Cardiovasc Surg, 2001. 122(5): p. 979-85; 19; Yaksh, T. L., et al., Intrathecal ketorolac in dogs and rats. Toxicol Sci, 2004. 80(2): p. 322-34], whereas the indwelling catheter/external pump is associated with scarring and infection [Jones, L. L. and M. H. Tuszynski, Chronic intrathecal infusions after spinal cord injury cause scarring and compression. Microscopy Research and Technique, 2001. 54(5): p. 317-324]. With a view toward developing a minimally-invasive drug delivery system that would provide sustained, local release of factors, a delivery paradigm is presented in which a drug loaded thermo-sensitive hydrogel is injected intrathecally and remains localized at the site of injection, delivering the drug load to the cerebral spinal fluid (CSF) with concomitant access to the brain and spinal cord [Jimenez Hamann, M. C., et al., Novel intrathecal delivery system for treatment of spinal cord injury. Exp Neurol, 2003. 182(2): p. 300-9] and then biodegrading, has been described. In this manner the hydrogel provides a platform for localized release over the life of the material. Evidence shows that intrathecal injection bypasses the dura and arachnoid mater and limits convective drug redistribution from CSF flow, all barriers that negatively impact epidural delivery [Chvatal, S. A., et al., Spatial distribution and acute anti-inflammatory effects of Methylprednisolone after sustained local delivery to the contused spinal cord. Biomaterials, 2008. 29(12): p. 1967-75]. Subsequently, a biocompatible and biodegradable blend of 2 wt % hyaluronan and 7 wt % methylcellulose (2:7 HAMC) has been developed for this application [Gupta, D., C. H. Tator, and M. S. Shoichet, Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. Biomaterials, 2006. 27(11): p. 2370-9]. The role of MC is to form a physical hydrogel through hydrophobic junctions [Schupper, N., Y. Rabin, and M. Rosenbluh, Multiple stages in the aging of a physical polymer gel. Macromolecules, 2008. 41(11): p. 3983-3994] and HA to increase solution viscosity and to enhance MC gel strength at lower temperatures through the salting out effect. 2:7 HAMC was found to degrade within 4-7 days in vivo, making it well suited for neuroprotective delivery strategies but unsuitable for drug delivery over the 2-4 weeks necessary for regenerative strategies [Kang, C. E., et al., A New Paradigm for Local and Sustained Release of Therapeutic Molecules to the Injured Spinal Cord for Neuroprotection and Tissue Repair. Tissue Eng Part A, 2008]. Accordingly, these injectable hydrogels were used to deliver erythropoietin [Kang, C. E., et al., A New Paradigm for Local and Sustained Release of Therapeutic Molecules to the Injured Spinal Cord for Neuroprotection and Tissue Repair. Tissue Eng Part A, 2008], as well as EGF and FGF-2 via simple diffusion [Jimenez Hamann, M. C., C. H. Tator, and M. S. Shoichet, Injectable intrathecal delivery system for localized administration of EGF and FGF-2 to the injured rat spinal cord. Exp Neurol, 2005. 194(1): p. 106-19]. For soluble molecules, the release profile is determined principally by diffusivity and occurs within 24 hours due to the short diffusive path length in vivo [Jimenez Hamann, M. C., C. H. Tator, and M. S. Shoichet, Injectable intrathecal delivery system for localized administration of EGF and FGF-2 to the injured rat spinal cord. Exp Neurol, 2005. 194(1): p. 106-19; Kang, C. E.; Tator, C. H.; Shoichet, M. S. 2010. Poly(ethylene glycol) Modification Enhances Penetration of Fibroblast Growth Factor 2 to Spinal Cord Tissue from an Intrathecal Delivery System J. Control Release; doi: 10.1016/j.jconre1.2010.01.029].
As mentioned above, U.S. parent patent application Ser. No. 11/410,831 describes a polymer matrix comprising an inverse thermal gelling polymer and an anionic polymer, for example HAMC that exists as a solid gel. This polymer matrix has a faster gelling rate than the inverse gelling polymer, and may be used alone or as a drug delivery vehicle for many applications. In particular, the polymer matrix can be used for localized, targeted delivery of pharmaceutical agents upon injection providing sustained release. A particular use of this invention is in delivery of a therapeutic agent to a fluid-filled space, such as the intrathecal space, in a highly localized, targeted manner, wherein the polymer matrix-contained therapeutic agent is able to circumvent the blood-spinal cord barrier or blood-brain barrier and enter the target tissue directly.
U.S. Pat. No. 6,335,035 ('035) to Drizen, et al. is a divisional of U.S. Pat. No. 6,063,405 to Drizen et al. which teaches sustained release compositions comprising a drug dispersed within a polymer matrix, methods of producing the same and treatments with the complex. The '035 patent discloses a sustained drug delivery system, which comprises a drug dispersed within a polymer matrix solubilized or suspended in a polymer matrix. The polymer matrix is composed of a highly negatively charged polymer material selected from the group consisting of polysulfated glucosoglycans, glycoaminoglycans, mucopolysaccharides and mixtures thereof, and a nonionic polymer selected from the group consisting of carboxymethylcellulose sodium, hydroxypropylcellulose and mixtures thereof. Nonionic polymers are generally used in amounts of 0.1% to 1.0% and preferably from 0.5% to 1.0%. Nonionic polymers in amounts above 1.0% are not used as they result in the formation of a solid gel product when employed in combination with an anionic polymer.
U.S. Pat. No. 6,692,766 to Rubinstein et al. concerns a controlled release drug delivery system comprising a drug which is susceptible to enzymatic degradation by enzymes present in the intestinal tract; and a polymeric matrix which undergoes erosion in the gastrointestinal tract comprising a hydrogel-forming polymer selected from the group consisting of (a) polymers which are themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes; and (b) polymers which are not themselves capable of enhancing absorption of said drug across the intestinal mucosal tissues and of inhibiting degradation of said drug by intestinal enzymes.
U.S. Pat. No. 6,716,251 to Asius et al. discloses an injection implant for filling up wrinkles, thin lines, skin cracks and scars for reparative or plastic surgery, aesthetic dermatology and for filling up gums in dental treatment. The invention concerns the use of biologically absorbable polymer microspheres or micro particles suspended in a gel.
U.S. Pat. No. 6,586,493 to Massia et al. discloses hyaluronate-containing hydrogels having angiogenic and vascularizing activity and pre-gel blends for preparing the hydrogels. The hydrogels contain a cross-linked matrix of a non-angiogenic hyaluronate and a derivatized polysaccharide material, in which cross-linking is effected by free-radical polymerization.
JP2003-342197 discloses a heat gelling pharmaceutical preparation containing methylcellulose and hyaluronic acid that is liquid at room temperature and gels upon administration to the eye.
The literature also teaches the properties of polymer matrices and their use as drug delivery vehicles (Xu et al. Langmuir, (2004) 20(3): 646-652, Liang et al. Biomacromolecules, 2004. 5(5):1917-25, Ohya et al. Biomacromolecules (2001) 2:856-863, Cho et al. International Journal of Pharmaceutics (2003) 260:83-91, Kim et al. Journal of Controlled Release (2002) 80:69-77, Tate et al. Biomaterials (2001) 22:1113-1123, and Silver et al., Journal of Applied Biomaterials (1994) 5:89-98).